Comparison of clinical outcomes, demographic, and laboratory characteristics of hospitalized COVID‐19 patients during major three waves driven by Alpha, Delta, and Omicron variants in Tehran, Iran

Abstract Introduction This study is the first study in which demographic, laboratory data, and outcomes of coronavirus disease‐2019 (COVID‐19) patients due to the circulating SARS‐CoV‐2 infections caused by different variants (Alpha, Delta, and Omicron) are compared in Iran. Methods We conducted a retrospective study of confirmed hospitalized COVID‐19 cases from April 9, 2021, to May 22, 2022. Demographic data and laboratory findings were extracted from patients' electronic medical records on the first day of admission to the hospital. All patients were followed up for outcomes related to COVID‐19 including intensive care unit (ICU) admission and mortality rate. Results Of 760 confirmed hospitalized COVID‐19 cases, 362, 298, and 100 represented patients during waves 4–6, respectively. During the Omicron wave, hospitalized patients were older than the other two waves and had a lower median level of C‐reactive protein (CRP), alanine transaminase (ALT), aspartate transaminase (AST), and erythrocyte sedimentation rate (ESR). The median length of hospital stay during waves 4–6 was 5 days (interquartile range [IQR]: 4.0–8.0), 7 days (IQR: 6.0–11), and 6 days (IQR: 5.0–9.0), respectively (p < 0.001). The rate of ICU admission during waves 4–6 significantly increased. Conclusions Although the Omicron variant caused less severe disease, in older patients who were hospitalized due to Omicron infection, longer hospital and ICU stays were reported, which could be attributed to their old age. In particular, elderly patients are more vulnerable to severe COVID‐19; otherwise, as expected, other laboratory parameters and clinical outcomes were in accordance with differences in pathogenicity and infectivity of these variants.

laboratory parameters and clinical outcomes were in accordance with differences in pathogenicity and infectivity of these variants.

K E Y W O R D S
COVID-19, epidemiology, Iran, mortality, variants, waves

| BACKGROUND
The world has faced a major public health challenge due to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as the cause of coronavirus disease-2019 (COVID- 19) and still, it is unclear when the pandemic will come to a complete end. 1 Until August 8, 2022, Iran has experienced seven waves of COVID-19 after the first confirmed case of SARS-CoV-2 in Iran on February 19, 2020. 2 Genetic analyses have revealed that the SARS-CoV-2 genome appears to be evolving relatively more slowly than others such as influenza viruses or HIV. 3 Gradually, several variants of SARS-CoV-2 have been introduced showing genetic differences from the original Wuhan strain, some of which are described as variants of concern (VOCs). 4,5 VOCs are attributed to induce multiple adverse consequences such as an increase in transmissibility or virulence, reduction in naturalizing antibodies, the ability to evade detection, and reduced effectiveness of therapeutics or vaccines.
Alpha, Beta, Gamma, Delta, and Omicron are classified as VOCs since the beginning of the pandemic. 4 Previous studies in Iran compared the first three waves of COVID-19 according to severity, intensive care unit (ICU) admission, and mortality rate with the main focus on the Alpha and Beta variants. 6,7 Nevertheless, to the best of our knowledge, no study describes the patients' characteristics in recent waves in the country driven by different variants.
The fourth wave in Iran began in early April-June 2021, and the fifth wave continued from August to October 2021. The sixth wave was from late January 2022 until now. 8 The dominant variant circulating during the fourth, fifth, and sixth waves of the COVID-19 in Iran was Alpha, Delta, and Omicron, respectively. 8 These waves of COVID-19 impose a more significant hospitalization and mortality rate than earlier waves. The fifth wave in August 2021 was one of the country's most devastating episodes of the pandemic, according to the report. 9 One observational study in Spain showed that patients' characteristics varied between different waves. 10 Currently, Omicron is the predominant variant circulating throughout the world. However, the severity and inhospital outcomes of this variant are not well characterized. 11 Numerous studies have explored the risk factors of SARS-CoV-2 infection and reported severity and long-term hospitalization associated with laboratory parameters such as elevated levels of creatinine, urea, and C-reactive protein (CRP). 12,13 This aim of this study is to describe the demographic data, laboratory parameters, and different in-hospital outcomes across the last three major waves of COVID-19 driven by Alpha, Delta, and Omicron variants in hospitalized patients in Tehran, Iran.

| Study design and participants
We performed a single-center retrospective study of proven hospital- The inclusion criteria for this study were (I) patients over 20 years of age diagnosed with COVID-19 by real-time polymerase chain reaction (PCR) and (II) those admitted to the hospital according to moderate to severe COVID-19 infection. We defined moderate and severe patients according to standard guidelines. Moderate patients are considered to have lower respiratory tract involvement with oxygen saturation (SpO 2 ) ≥ 94% on room air at sea level. Patients with oxygen saturation (SpO 2 < 94%) on room air, oxygen partial pressure (PaO 2 )/ fractional inspired oxygen (FiO 2 ) ratio < 300 mmHg, a respiratory rate > 30 breaths/min, or lung infiltrates > 50% are defined as severe COVID-19 infection. We also included other criteria such as the need for intubation and admission to the ICU, which were monitored throughout the patients' hospitalization. Patients who were not admitted for COVID-19 and children younger than 20 were excluded from the study. All patients in three waves received glucocorticoid and anticoagulant therapy.
Demographic data and laboratory findings were extracted from patients' electronic medical records on the first day of admission to the hospital. All patients were followed up for outcomes related to COVID-19 including ICU admission and mortality rate. We categorized patients into the last three waves based on reports that recognized distinct waves in different months in Iran. 8,14 The fourth wave in Iran was defined as the period from April 9 to June 10, 2021, the fifth wave was defined as the period between August 9 and October 10, 2021, and the sixth wave was defined as the period between January 20 and May 22, 2022. Variant-specific PCR was used for the validation of SARS-CoV-2 variants in the community.

| Statistical analysis
Categorical variables were presented as counts and frequencies and then compared using the chi-square test. To assess the normal distribution of numerical variables, we used the Kolmogorov-Smirnov and Shapiro-Wilk tests. Normally distributed numerical variables were presented as mean ± SD and compared using the one-way analysis of variance (ANOVA) test. Variables with skewed distributions were presented as median (interquartile range [IQR]) and compared using the Kruskal-Wallis test. All statistical analyses were conducted using SPSS Statistics for Windows Version 21. We considered p < 0.05 to be statistically significant.

| Clinical characteristics and laboratory data
Clinical presentation among hospitalized patients with COVID-19 did not show significant differences between these three waves. However, the most frequently reported clinical symptoms were fever, dyspnea, cough, chest pain, myalgia, and headache (not shown). The laboratory findings at admission are outlined in Table 1. There were  to-lymphocyte ratio ( p < 0.001), and magnesium ( p < 0.001) levels of patients between the waves. However, blood sugar ( p = 0.3) and calcium ( p = 0.06) were not significantly different in patients admitted in the three waves. Statistical analysis showed that patients in wave 6 had significantly higher urea, creatinine, neutrophil-to-lymphocyte ratio, and platelet and lower CRP, AST, and ALT than the two other waves.

| In-hospital outcomes and clinical complications
The median length of hospital stay for the fourth, fifth, and sixth Comparing ICU length of stay showed that the ICU length of stay during wave 6 was longer than the other ones (p = 0.008). The percentage of ICU, deceased patients, and length of hospital stay for the three waves are presented in Figure 1. Omicron has milder symptoms than the Delta variant, but older people are still at risk of serious complications because their immune system is not as strong and antibody levels are usually insufficient to fight such mutant viruses. 24 Interestingly, we observed a greater length of stay in the ICU and a high rate of ICU admission in the elderly group during the Omicron wave compared with the other two waves, which is contrary to Jassat et al. 27 and Sievers et al. 28 who showed that ICU admission during the Omicron wave was lower than earlier waves. In our study, most of the patients (more than 70%) who were admitted to the hospital during the Omicron wave were elderly patients. One recent study concluded that elderly were more susceptible to infection with the Omicron variant, even in fully vaccinated individuals. 24 Therefore, this age group needed more critical care and referral to ICU. 29 Among admitted elderly patients during the Omicron variant, 78.3% of patients were referred to ICU. Unfortunately, we had no access to underlying disorder data, so it was not clear how many of these patients had comorbidity, which affected COVID-19
During the Delta predominance era, a small percentage of Iranians had been fully vaccinated that might be linked to severe symptoms and in-hospital mortality. In this regard, consistent with previous studies, elevated CRP, erythrocyte sedimentation rate (ESR), ALT, and AST as laboratory parameters for the severity of COVID-19 were observed in the Delta variant. 30,31 One probable cause for higher hepatic transaminases could be attributed to adverse effects from multi-drug therapy during the fifth wave than the other two waves. However, magnesium was slightly higher during Alpha than in the other two waves due to the anti-inflammatory and antithrombotic effects of Mg 2+ that were related to reducing the severity of COVID-19 symptoms. 32 An increase in urea and creatinine levels during the Omicron wave could be related to increasing age in hospitalized patients during this period. 33,34 In the sixth wave by the Omicron variant, regardless of vaccination status, the majority of infected individuals were young asymptomatic outpatients while patients with comorbidities and elderly patients had a high risk for severe COVID-19 and hospitalization. 35,36 According to this point, in the present study, elderly patients com-

ACKNOWLEDGMENTS
The authors would like to thank all healthcare workers from the Valiasr Naja Hospital, Tehran, Iran, for their efforts against COVID-19.

CONFLICT OF INTEREST STATEMENT
The authors declare that there are no conflicts of interest.

PEER REVIEW
The peer review history for this article is available at https://www. webofscience.com/api/gateway/wos/peer-review/10.1111/irv.

DATA AVAILABILITY STATEMENT
All data are available from the corresponding author upon reasonable request.

ETHICS STATEMENT AND CONSENT TO PARTICIPATE
The study was conducted in accordance with the Declaration of